Method of tranquilization employing 10-chloro deserpidine



Nov. 15, 1966 l.. vELLUz ETAL 3,285,815

METHOD OF TRNQUILIZATION EMPLOYING 10CHLORO DESERPIDINE Mlm/EL Paty/wmf G50/MES Mu L L 5,@

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Nov. 15, 1966 1 vELLUz ETAL 3,285,815

METHOD OF TRANQUILZATION EMPLOYING lO-CHLORO DESERPIDINE IN VEN TORS 6o/v l/eLu/z 47085.91- J/Qu/e' B Y M1 cua Perse/C44 w GEORGES NU LLER SWA u. www@ AGENT United States Patent O 2 Claims. (ci. 167-65) The present invention relates to new tranquilizer compositions and more particularly to new tranquilizer cornpositions containing, as active agent, -chloro deserpidine, and to a process of using such compositions 1n therapy.

The present application is a continuation-in-part of copending application Serial No. 727,777, filed April 1l, 1958, now abandoned.

The valuable neuro-depressive activity of reserpine is well known. This activity, however, is accompanied by a number of disadvantages. While it suppresses in pathological cases a number of useless and undesired reactions due to its tranquilizing effect, it also has a depressive effect upon those functions necessary for carrying out useful or desired physiological reactions. Frequently it produces drowsiness and disinterestedness to the outside world, sometimes even profound apathy.

It is one object of the present inventionto provide new tranquilizer compositions which avoid all the inconveniences and disadvantages and especially the neuro-depressive effects encountered on administration of reserpine, while retaining all the desirable tranquilizing effects ordinarily achieved by reserpine.

Another object of the present invention consists in providing a process of tranquilizing patients by administration of such new and valuable pharmaceutical compositions.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

10-chloro deserpidine, the active agent according to the present invention, is prepared according to -the process described in copending patent application Serial No. 727,777, filed April 11, 1958, now abandoned.

Investigations were carried out to separate these two effects, the desired tranquilizing effect and the undesired neuro-depressive effect, and, thus, `to supply products which will be useful as tranquilizers but which, at the same time, have only an insignificant depressive activity, i.e. which do not affect normal behavior.

To test such compounds, the amphetamine test as described by L. Lasagna and W. P. McCann Science, vol. 125, page 1241 (1957), and by l. H. Burn and R. Hobbs, Arch. Int. Pharmacodyn., vol. 113, page 290 (1958), was used. This test is based on the known fact studied more particularly by Chance, that the mortality rate in mice, due to the administration of amphetamine, is considerably increased if the animals are kept in groups instead of being isolated in individual boxes. This significant increase in mortality rates is caused by the transmission of the state of excitement from one mouse to another. Their aggressiveness and their panic-like fear induce fatal paroxysms when kept in groups. The capacity of a drug of reducing this significant increase in mortality, due to the confinement of the animals, defines and determines according to said test, the tranquilizing activity of the drug.

Simultaneous presence of tranquilizing activity and generfal neuro-depressive activity prevents rational exploita- 3,285,815 Patented Nov. 15, 1966 ice tion of the first mentioned property, which, from the therapeutic view point, is of greater interest.

The new pharmaceutical compositions according to the present invention possess very remarkable tranquilizing activity without exerting undesirable neuro-depressive effects.

According to the present invention, it has been found quite surprisingly that it is possible to dissociate said two activities of reserpine by using an analogous compound, namely, 10-chloro deserpidine. This compound has a tranquilizing effect which is substantially equal to that of reserpine, while it exerts only a negligible depressive eect on the central nervous system. Its depressive activity is only about one-tenth to one fortieth of that of reserpine. Compositions Ibased on l-chloro deserpidine possess also a considerably lower toxicity than reserpine. Furthermore, the sensitizing effect of reserpine induced by cerebral electrical excitation of the brain and by maximum electric shock treatment is also found to be very much lower with the new compositions according to the present invention than with reserpine.

Consequently, the present invention provides a drug of the'reserpine series which is a highly effective and reliable tranquilizer without exerting a general neuro-depressive effect.

Other advantages of this invention will be apparent to specialists in the field.

In principle, pharmaceutical compositions according to the present invention are prepared by combining 10-chloro deserpidine with the appropriate pharmaceutical excipients which may be solid or liquid. Solid compositions may be in the form of tablets, lozenges, coated tablets or dragees, pills, capsules, or powders, or in the form of fluid preparations such as solutions, emulsions, suspensions, sirups, or elixirs.

They may also be used in the form of suppositories or may be administered in any other form.

In the case of powders, a fine dispersion of the active compound is of importance for accuracy in dosage. Such a ne dispersion can be achieved, for instance, by intimately mixing and milling the compound in a ball mill with a solid, pulverulent extending agent to the desired degree of fineness or by impregnating the already milled, finely powdered, solid carrier with a mixture of the active compound dissolved in water or any other suitable solvent and then removing the water or solvent.

To prepare the solid shaped compositions such as tablets, pills, lozenges, and other solid forms suitable for administration of the active agent, the conventional extending, diluting, binding agents, lubricants, and other tableting adjuvants such as sugar, lactose, sorbitol, talc, starch, pectin, gelatin, gum arabic, methyl cellulose, carboxy methyl cellulose, preferably in the form of its sodium salt, yeast extracts, agar, calcium sulfate and cal- .cium carbonate, kaolin, stearic acid, magnesium stearate,

and/or solubilizing agents such as alcohol, chloroform, trichloro ethylene, and the like are used.

The content of active principle in these compositions may vary. It is, of course, necessary that the active compound be present in such an amount that a suitable dosage will be ensured per dosage unit. The content of the new compositions may be between about 0.01% and about 10%. Larger amounts may, of course, also be incorporated although with such larger amounts accurate dosing will be more difficult.

The average dose is between `about 0.1 mg. and 10.0 mg. per day, taken subdivided in 3 or 4 doses, but daily doses as high as 30 mg. can be taken without danger, if necessary.

It is also to be understood that 10-chloro deserpidine may be used in combination with other drugs or may be administered to solid or liquid foods without exceeding the scope ofthe present invention.

The following examples and experimental results will serve to illustrate the present invention, without, however, limiting the same thereto. In all of the examples the levorotatory enantiomorph of l-chloro deserpidine is used as active agent.

EXAMPLE 1.-PREPARATION OF TABLETS 100 g. of 10-chloro deserpidine are mixed with 400 g. of sugar, 8,870 g. of lactose, 4,600 g. of starch, and 130 g.

The mortality percentages obtained by totaling all the tests of Table I produce an almost linear function when the logarithm of the dose injected is plotted graphically. The slope of the straight line thus obtained is slight, indicating gradual eiects over an extended posologie zone. The attached graph FIG. 1 illustrates these results.

In order to compare quantitatively the tranquilizing effect of 10-chloro deserpidine and of reserpine, tests on 220 mice were carried out simultaneously under the same conditions as described above with these two products, The result of these tests are shown in Table II.

TABLE II.-COMPARISON OF THE EFFECT OF 10-CHLORO DESERPIDINE AND OF RESERPINE, INJECTED INTRAPERITONEOUSLY, ON THE MORTALITY OF GROUPS OF TEN MICE WHICH RECEIVED, ALSO INTRA- PERITONEOUSLY, 40 MGJKG. OF AMPHETAMINE of 4 gelatin. The resulting homogeneous powder is moistened, granulated, and forced through an apertured plate or a sieve of screening wire of adequate dimensions.

After drying, the granulated material is ground; then lubricated lby the addition of 750 g. of talc and 150` g. of magnesium stearate. The mixture is then compressed to tablets weighing 150 mg. each and containing l mg. of active principle.

EXAMPLE 2.-PREPARATION OF A SOLUTION 0.4 g. of 10-chloro deserpidine are mixed with 4 g. of tartaric acid, 18 g. of benzyl alcohol, 400 cc. of polyethylene glycol 400,V and with a quantity of distilled water suicient to produce a volume of 2000 cc.

The solution thus prepared contains 0.4 mg. of active agent per 2 cc. It is administered both by intravenous and intramuscular injection.

EXAMPLE 3.-TESTS ON ANIMALS 1. Tests of tranquilizz'ng activity by intraperitoneal injection A 40 mg./kg. dose of amphetamine when injected intra-peritoneously into groups of ten mice produced an average mortality of 88%. The compounds of the -reserpine series to be compared are administered, also by .intraperitoneal injection, 11/2 hours before the injection of amphetamine. Each test included a group of l0 control animals which, in place of active agent, received solely .the solvent, likewise 11/2 hours before amphetamine injection.

The results obtained on administration of varying amounts of 10-chloro deserpidine are given in Table I.

, A indicates 10-chlor0 deserpidine.

B indicates reserpine.

The attached graph FIG. 2 illustrates the results obtained in these comparative tests and shows that the two compounds have about the same tranquilizing activity.

II. Test for depressive activity l In this test the depressive activity was determined by the tumbling eiect on mice placed in groups of 5 in la horizontal cylinder rotating about its axis. The untreated mice were able to maintain their equilibrium by placing themselves contrary to the movement of the cylinder. The speed of the cylinder was adjusted in such a manner that the number of falls per animal did not exceed four during a four-minute te-st. The abatement of the reflexes increases the number of falls in a manner obviously in relation to the dose of active agent injected, thus making it possible to evaluate the intensity of the Iaction of the product to be tested.

The mice are observed one hour or, respectively, four hoursl after intraperitoneal injection of the compound to be tested and once every day on four subsequent days. The attached graph FIG. 3 shows the results obtained in this test with 10-chloro deserpidine as compared with reserpine.

The amounts injected intraperitoneously are indicated in mg./ kg. at the beginning of each curve.

This graph FIG. 3 proves that the depressive state caused by a dose of 20 mg./kg. of 10-chloro deserpidine is scarcely more pronounced than that produced by the TABLE I.-EFFECTS OF IO-CHLORO DESERPIDINE, INJECTED INTRA- PERITONEOUSLY, ON THE MORTALITY OF GROUPS OF l0 MICE, WHICH RECEIVED, ALSO INTRAPERITONEOUSLY, 40 MGJKG. OF

J this test with 10-chloro deserpidine as compared with reserpine.

The test used to determine the threshold of sensitivity to electric shock in rats is that described by Woodbury and Davenport Arch. Int. Pharmacodyn, vol. 92, page 97 (1952).

10-chloro deserpidine and reserpine are injected intraperitoneally in various doses. Table VI shows the average threshold values observed in groups of 10 rats.

TABLE vI.-CoMPARIsoN F THE EFFECT oF lcCHLoRo DESERPIDINE AND oF REsERPrNE oN THE THREsH- (llSVAl/UE OF SENSITIVITY TO ELECTRIC SHOCK IN It is evident that reserpine considerably lowers the electric shock threshold values in doses of 2 mg./kg. and 5 mg./ kg. Whereas 10-chloro deserpidine, even when used in a dose of 5 mg./kg. only causes a lowering of the threshold value comparable to that of 0.5 mgJkg. of reserpine.

The increased sensitivity of patients treated with reserpine to electric shock is well known. It Vwas of interest, therefore, to determine whether -chloro deserpidine would have a similar modifying effect on the maximum crisis of rats as reserpine. As is shown by the Vfollowing Table VII, reserpine increases the number of maximum crises already Iby intraperitoneal administration of a dose of 0.5 mg./kg. In contrast thereto 10-chl0ro deserpidine produces a comparable increase only with a dose of 5 mg./kg. under the same conditions.

TABLE VIL-COMPARISON oF THE EFFECT @F10-CHLOE() DESERPIDINE AND RESERPINE oN THE FREQUENCY OF OCCURRENCE oF MAXIMUM CRIsEs IN RATS SUB- JECTED To AN ELECTRIC SHOCK TREATMENT WITH A CURRENT OF 180 V. (CORRESPONDING TO 20 M. AMP. UNDER THE CONDITIONS OF THIS EXPERIMENT) VI. Toxicity (a) Acute toxcty.-10-ch1oro deserpidine, injected intraperitoneally, does not cause any death in mice until a dose of mg./l g. is administered. This corresponds to the toxicity of the solvent used. A supplementary test was carried out using a suspension and administering 50 mg./kg.; 100 mg./kg.; 250 mg./kg.; 1 g./kg.; and 1.5 g./kg. Only the two highest doses resulted in death 7 to 11 days after the injection (-4 out of :l animals died on administration of 1 g./kg. and 5 out of 5 animals on administration of 1.5 g./kg., the mice ybeing in a state of profound prostration until death).

The margin 0f safety is thus very considerably superior to that of reserpine whose DLG when administered intraperitoneally in suspension is 7 mg./ kg. under the same experimental conditions.

(b) Chronic toxicity-6 groups of 10 young rats, each weighing, as an average, 10 g., received daily (except Sundays) for a month a subcutaneous injection of 10- chloro deserpidine or, respectively, of reserpine in the following doses:

Group 1, controls: no treatment;

Group 2: 10-chloro deserpidine, 0.2 mg./kg.; Group 3: 10-ch1oro deserpidine, 0.5 mg./kg.; Group 4: 10-chloro deserpidine, 1 mg./kg.; Group 5 reserpine, 0.2 mg./ kg.;

Group 6: reserpine, 0.5 mg./kg.;

Reserpine caused a pronounced inhibition of growth in the doses employed and, with the dose of 0.5 mg./kg., even a loss of weight. Furthermore, 3 rats of group 5 and 2 rats of group 6 died.

The 3 groups treated with the various doses of l0-ch loro deserpidine showed, after a month of treatment, weight curves superimposable on those of the controls and their general state was satisfactory in all regards.

All these tests prove that 10-chloro deserpidine is a far better tranquilizing agent than reserpine and that its toxicity and its potentiating effect on barbiturates are very surprisingly lower than those of reserpine. The new compositions, thus, represent a highly meritorious advance in the tranquilizer art.

It is, of course, understood that, in place of 10-chloro deserpidine, its non-toxic, therapeutically active acid addition salts, such as the salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, tartaric acid, ascorbic acid, methane sulfonic acid, hydroxy ethane sulfonic acid, p-toluene sulfonic acid, salicylic acid, p-amino salicylic acid, acetyl salicylic acid, nicotinic acid, and others can also be employed in the tranquilizing compositions, according to the present invention.

EXAMPLE 4 The active agent 10-ch1oro deserpidine is obtained by proceeding, for instance, in the following manner:

5-chloro tryptamine is prepared as described by Abramovitch in 1. Chem. Soc. 1966, page 4599. It is purified by dissolving it in methylene chloride, passing carbon dioxide into the solution, and decomposing the separated addition product by heating.

Eqimolecular amounts of the purified 5-chloro tryptamine and of the methyl ester of l-carboxy methyl-2pmethoxy carbonyl-3a-methoxy-4j8-acetoxy-G-formyl cyclohexane are allowed to stand at room temperature for 15 minutes'. Thereby, a solution of the methyl ester of 10- chloro 16-meth0xy carbonyl-17-methoXy-18-acetoxy- (2-3 3-4) -diseco-A4f21,20a-yohimbene-3carboxylic acid is obtained which is used without further purication in the following reaction step.

22 cc. of methanol are added to said methylene chloride solution obtained from 1 g. of 5-chloro tryptamine. After cooling the mixture to +5" C., 1 g. of potassium boronhydride is added. The temperature of the mixture is maintained at |5 C. for 15 minutes and then at `-j-20" C. for 30 minutes. Excess boronhydride is destroyed by the addition of the minimum required amount of acetic acid. The solution is evaporated to dryness in a vacuum at a temperature not exceeding 20 C.

The residue is taken up with acetone. The solution is filtered and concentrated by distillation to a small volume. Ether is added and crystallization is initiated by scratching. After'cooling in ice, the crystals are filtered off with suction. 10-chloro-18-acetoxy-16-methoxy carbonyl-17a-methoxy-3-oxo-Z,3-seco-20e-yohimbane is obtained thereby,

administration `ot 1 -mg/kg. of reserpine and that the effect of 50 mg./kg. of 10-chloro deserpidine is much weaker than t-hat with 5 mg./ kg. of reserpine.

10-chloro deserpidine, therefore, only exerts a depressive effect of about one-twentieth that of reserpine.

III. Eyelid drooping test This test is based on the property possessed by compounds of the reserpine series of causing the eyelids to droop. The intensity of this effect is measured bythe degree of narrowing of the palpebral slit, defined according to the scale a-s proposed by Ruben et al. 1. Pharmacol. Exp. Therap, vol. 120, page 125 (1957).

Grade =no visible effect;

Grade l: closing of the palpebral slit by one-fourth; Grade 2=closing the palpebral slit by one-half;

Grade 3=closing of the palpebral slit by three-fourths; Grade 4=complete closing the eyelids.

By adding the grade numbers determined on examining the eyes of a group of 5 rats according to the above given scale, whereby the total grade numbers may vary between 0 and 40, the degree of sedation can be expressed as of any given moment after injection.

Table III shows the grade numbers obtained on taking readings 5 hours or, respectively, 6 hours after intraperitonal injection into rats of varying doses of -chloro deserpidine and of reserpine. Th'e effect `of each dose reached its maximum at the moment of said readings and then stayed on a slightly fluctuating level. By combining said two values expressed in percentage of the highest lpossible eect, it is possible to calculate the ED50 (50% effective dose) according to the graphic method of Miller -and Tainter. A comparison of the two ED50 proves that 10-chloro deserpidine has only one-tenth of the effect of reserpine.

6 It may be especially pointed out that in mice the tranquilizing effect of 10-chloro deserpidine has been established and has been found to be substantially equal to that of reserpine.

IV. Potentalzaton of the hypnotic ect of barbtumtes It as well known that compounds of the reserpine series cause prolongation of sleep induced by barbiturates. The following experiment was carried out in order to determine whether or not 10-chloro deserpidine possesses l this property.

Amytal was employed as barbiturate by reason of the brevity of its action when used alone.

l0-chloro deserpidine and reserpine were injected peritoneally into mice in groups of l0 mice. A dose of 80 mg./kg. of amytal was injected intravenously to one grou pof 10 mile serving as controls. The other group of mice received 1%. hours before administration of amytal either 10-chloro deserpine or reserpine. The duration of sleep was determined by the interval of time between the injection of amytal and thereappearance of the getting up reex, whereby the mice returned to their upright position.

Y The results obtained thereby are shown in, Table V, which indicates the duration of sleepin minutes for the two compounds according to the dose administered.

It is evident that while reserpine with doses of 0.5 mg./kg. and 2 Ing/kg.v significantly increases the duration of sleep induced by amytal, 10-chloro deserpidine at the same doses, does not produce any significant increase in duration of sleep, when, of course, allowance is made for individual variations in animals receiving amytal only. I

TABLE IIL-COMPARISON OF THE EFFECT OF lO-CHLO RO DESERPIDINE AND OF RESERPINE IN THE EYELID DROOPING TEST IN RATS ED of l-cliloro deserpidine=2-40 mg./kg.;i;0.45 nig/kg'. ED50 of reserpine=0.260 mg./kg.:i;0.019 Ing/kg.

When using mice as test animals (see Table IV) the difference between the effects of the two compounds is even greater. 10-chloro deserpidine has an eyelid drooping effect of only one-fortieth of that of reserpine.

TABLE IV.-COMPARISON 0F THE ACTION OF lo-oHLoRO DESERPIDINE AND OF RESERPINE IN CAUSING EYE- LID DROOPING IN MICE Dose in 5 hours 6 hours Average Compound injected ing/kg. after after effect injection injection per dose 10-ehloro deserpidine 1 3 2 6 2 Reserpine 0. 1 12 8 25 E135@ of 10-ehloro deserpidine=7 mg./kg.=i:1.7 ing/kg. EDan of reserpine=0-175 Ing/kg. :110.029 nig/kg.

TABLE V.ACTION OFvlO-CHLORO DESERPIDINE AND OF RESERPINE ONKTHE DURATION OF SLEEP INDUCED BY AMYTAL IN MICE Compound injected Time of sleep in minutes Amytal alone mg./kg 51:i;9 ltlehloro deserpidine 0.5 nig/kg. plus amytal- 68i17 lehloro deserpidine 2 mglkg. plus amytaL.- 53:i;7 Reserpine 0.5 mg./kg. plus amytal 101119 Reserpine 2 mglkg. plus amytal 1505220 V. Electric shock test on rats It is well known that reserpine lowers the threshold of sensitivity to electric shock. This effect may be in relation to trembling and particular spastic symptoms in animals treated with high doses of reserpine. It may also be the cause of certain undesirable clinically observed effects during the course of treatment with this alkaloid.

The following experiment shows the results obtained in This compound is saponied by means of N-sodium hydroxide solution by heating with stirring to 85 C. for one and one half hour, cooled, and rendered acid to a pH of 4.0 by the addition of acetic acid. The clear solution is extracted with methylene chloride in order to remove colored impurities. After decanting the organic layer, the aqueous layer is cooled in ice for one hour. The precipitated crystals of 10-chloro-1-carboxy-17a-methoxy-18- hydroxy-3oxo-2,3-seco-20ot-yohimbane are ltered with suction, washed with water, and dried at 40 C. Melting point 180-190 C.; rotatory power {0&1}320: -l-31 (concentration: 0.5% in ethanol).

Said carboxylic acid is pasted with methanol and a solution of diazomethane in methylene chloride, is added in small portions to said paste until the color of the reaction mixture remains yellow.l The resulting solution is evaporated to dryness in a vacuum at 20 C. and the residue is taken up in acetone. Thereby, 10-chloro-16-methoxy carbonyl 17u-methoxy-18-hydroxy-3-oxo-2,3seco20otyohimbane is obtained.

This compound is dissolved in a mixture of pyridine and triethylamine (3: 1). Nitrogen is passed through the solution and an excess of 3,4,5-trirnethoxy benzoic acid anhydride is added thereto. The mixture is heated to 95 C. for 24 hours. After cooling, excess anhydride is destroyed by the addition of water. Methylene chloride and ice are added and the reaction mixture is acidified to a pH of 1.0 by the addition of hydrochloric acid. The organic layer is separated, washed with a sodium bicarbonate solution, dried, and evaporated to dryness. The residue is dissolved in a mixture of ethyl acetate and ether. On cooling in an ice bath for half an hour, 10-chloro-17a-methoxy-16- methoxy carbonyl-18-(3,4,5-trimethoxy benzoyloxy) 3-oxo-2,3-seco-20a-yohimbane is obtained.

Said ester is reuxed with about 5 times its amount of phosphorus oxychloride for one hour. The mixture is evaporated to dryness in a vacuum and the residue is taken up with methanol. 65% perchloric acid (d.=1.6l) and, thereafter, Water are added to the solution while cooling. The yellow precipitate of the perchlorate of -chloro- 17a methoxy 16,6 mcthoxycarbonyl-18(3,4,4tri methoxy benzoyloxy)-A3(4),20ayohimbane is filtered olf with suction and washed with water.

The crude perchlorate is mixed with acetone, tetrahydrofuran, aqueous 13% perchloric acid solution, a small amount of ferric chloride, and zinc powder. The mixture is reiluxed for 30 minutes and then filtered. The filtrate is concentrated by evaporation, mixed with water, and extracted with methylene chloride. The extracts are washed with dilute ammonia solution, dried over magnesium sulfate, and evaporated to dryness. The residue is dissolved in methanol. After the addition of 0.5 cc. of dilute nitric acid, the solution is cooled and crystallization. is initiated by scratching. The yellow crystals of the nitrate of 10- chlhoro deserpidine are filtered off by suction and are suspended in methanol. On adding ammonia, 10-chloro deserpidine crystallizes. It is ltered, Washed with methanol, and dried. The resulting 10-chloro deserpidine, i.e. 10- chloro 17a methoxy 18/3-(3',4',5'-trimethoxybenzoyloxy) 16,9 methoxy carbonyl-3[3,20a-yohimbane crystallizes with 1/2 mole of water and has a melting point of -170" C. and a rotatory power of [M1320: 147 (concentration: 0.5% in chloroform), and is insoluble in water and ether, slightly soluble in benzene, and soluble in acetone and chloroform.

We claim:

1l. The process of tranquilizing persons and animals without exerting a substantial depressing effect upon the central nervous system, said process consisting in administtering to persons and animals a compound selected from the group consisting of 10-chloro deserpidine and its therapeutically active acid addition salts in an amount between about 0.1 ing/kg. and about 0.5 mg./.kg per day.

2. The process of tranquilizing persons and animals without exerting a substantial depressing eect upon the central nervous system, said process consisting in administering to persons and animals the levo-rotatory 10chloro deserpidine in an amount between about 0.1 ing/kg. and about 0.5 nig/kg. per day.

References Cited by the Examiner UNITED STATES PATENTS 2,857,385 10/1958 Kuehne 260-236 2,872,377 2/1959 Beiler 167-67 2,912,436 11/1959 Weisenborn 260-287 OTHER REFERENCES Barsa: Am. I. of Psychiatry, vol. 114, July 1957, p. 74.

Rossi: Am. J. Pharm., vol. 129, No. 2, pp.. 53 and 58, February 1957.

Drug and Cosmetic Industry, vol. 78, No. 4, p. 461, April 1956.

J.A.P.A., Prac. Pharm. Ed., June 1957, pp. 382-383.

JULIAN S. LEVITT, Primary Examiner.

WLLIAM B. KNIGHT, MORRIS O. WOLK, IRVING MARCUS, Examiners.

I. S. SAXE, P. SABATINE, S. ROSEN,

Assistant Examiners. 

1. THE PROCESS OF TRANQUILIZING PERSONS AND ANIMALS WITHOUT EXERTING A SUBSTANTIAL DEPRESSING EFFECT UPON THE CENTRAL NERVOUS SYSTEM, SAID PROCESS CONSISTING IN ADMINISTERING TO PERSONS AND ANIMALS A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 10-CHLORO DESERPIDINE AND ITS THERAPEUTICALLY ACTIVE ADDITION SALTS IN AN AMOUNT BETWEEN ABOUT 0.1 MG./KG. AND ABOUT 0.5 MG./KG PER DAY. 